tbuckley/cabot-search huggingface dataset:
Molecular Mechanisms and Future Implications of VEGF/VEGFR in Cancer Therapy
Authors: Sonia A. Patel, Monique B. Nilsson, Xiuning Le, Tina Cascone, Rakesh K. Jain, John V. Heymach
Journal: Clinical Cancer Research (2022)

Abstract Angiogenesis, the sprouting of new blood vessels from existing vessels, is one of six known mechanisms employed by solid tumors to recruit blood vessels necessary for their initiation, growth, and metastatic spread. The vascular network within the tumor facilitates the transport of nutrients, oxygen, and immune cells and is regulated by pro- and anti-angiogenic factors. Nearly four decades ago, VEGF was identified as a critical factor promoting vascular permeability and angiogenesis, followed by identification of VEGF family ligands and their receptors (VEGFR). Since then, over a dozen drugs targeting the VEGF/VEGFR pathway have been approved for approximately 20 solid tumor types, usually in combination with other therapies. Initially designed to starve tumors, these agents transiently “normalize” tumor vessels in preclinical and clinical studies, and in the clinic, increased tumor blood perfusion or oxygenation in response to these agents is associated with improved outcomes. Nevertheless, the survival benefit has been modest in most tumor types, and there are currently no biomarkers in routine clinical use for identifying which patients are most likely to benefit from treatment. However, the ability of these agents to reprogram the immunosuppressive tumor microenvironment into an immunostimulatory milieu has rekindled interest and has led to the FDA approval of seven different combinations of VEGF/VEGFR pathway inhibitors with immune checkpoint blockers for many solid tumors in the past 3 years. In this review, we discuss our understanding of the mechanisms of response and resistance to blocking VEGF/VEGFR, and potential strategies to develop more effective therapeutic approaches.
Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results
Authors: Christine D. Palmer, Amy R. Rappaport, Matthew J. Davis, Meghan G. Hart, Ciaran D. Scallan, Sue-Jean Hong, Leonid Gitlin, Lauren D. Kraemer, Sonia Kounlavouth, Aaron Yang, Lindsey Smith, Desiree Schenk, Mojca Skoberne, Kiara Taquechel, Martina Marrali, Jason R. Jaroslavsky, Charmaine N. Nganje, Elizabeth Maloney, Rita Zhou, Daniel Navarro-Gomez, Adrienne C. Greene, Gijsbert Grotenbreg, Renee Greer, Wade Blair, Minh Duc Cao, Shawn Chan, Kyounghwa Bae, Alexander I. Spira, Sameek Roychowdhury, David P. Carbone, Brian S. Henick, Charles G. Drake, Benjamin J. Solomon, Daniel H. Ahn, Amit Mahipal, Steve B. Maron, Benny Johnson, Raphael Rousseau, Roman Yelensky, Chih-Yi Liao, Daniel V. T. Catenacci, Andrew Allen, Andrew R. Ferguson, Karin Jooss
Journal: Nature Medicine (2022)
The short inverted repeats-induced circEXOC6B inhibits prostate cancer metastasis by enhancing the binding of RBMS1 and HuR
Authors: Cong Zhang, Shiyu Wang, Fan Chao, Guojin Jia, Xuanguang Ye, Dunsheng Han, Ziwei Wei, Jinke Liu, Guoxiong Xu, Gang Chen
Journal: Molecular Therapy (2022)

Circular RNAs (circRNAs) are a novel class of endogenous RNAs with a covalently closed loop structure. Many circRNAs have been found to participate in cancer progression. However, the detailed generation process, functions, and related mechanisms of circRNAs in prostate cancer (PCa) remain largely unknown. In the present study, we identified circEXOC6B, a novel suppressor in the metastasis of PCa. Functionally, circEXOC6B, originating from the exocyst complex component 6B (EXOC6B) gene, inhibited migration and invasion of PCa in vitro and in vivo. Mechanistically, by acting as a protein scaffold, circEXOC6B enhanced the binding of human RNA binding motif single strand interacting protein 1 (RBMS1) and human antigen R (HuR) and further increased A-kinase anchoring protein 12 (AKAP12) expression to inhibit PCa metastasis. Unlike previous studies, we found that one pair of short inverted repeats in flanking introns at least partly promoted the circularization of circEXOC6B. Our study presents a novel mechanism for the inhibitory role of circEXOC6B in PCa metastasis and provides new insight into the molecular process of circRNA generation. Circular RNAs (circRNAs) are a novel class of endogenous RNAs with a covalently closed loop structure. Many circRNAs have been found to participate in cancer progression. However, the detailed generation process, functions, and related mechanisms of circRNAs in prostate cancer (PCa) remain largely unknown. In the present study, we identified circEXOC6B, a novel suppressor in the metastasis of PCa. Functionally, circEXOC6B, originating from the exocyst complex component 6B (EXOC6B) gene, inhibited migration and invasion of PCa in vitro and in vivo. Mechanistically, by acting as a protein scaffold, circEXOC6B enhanced the binding of human RNA binding motif single strand interacting protein 1 (RBMS1) and human antigen R (HuR) and further increased A-kinase anchoring protein 12 (AKAP12) expression to inhibit PCa metastasis. Unlike previous studies, we found that one pair of short inverted repeats in flanking introns at least partly promoted the circularization of circEXOC6B. Our study presents a novel mechanism for the inhibitory role of circEXOC6B in PCa metastasis and provides new insight into the molecular process of circRNA generation.
Remarkably Widened QRS Complex Following a Lethal Dose of Propafenone—An Ominous Sign
Authors: Jing-Xiu Li, Mu-Qiu Wang, Min Gao
Journal: JAMA Internal Medicine (2022)

This case report describes the electrocardiogram findings of a patient in their 30s who attempted suicide by taking propafenone and presented to the emergency department with impaired consciousness and convulsions.
Risk of SARS-CoV-2 Acquisition in Health Care Workers According to Cumulative Patient Exposure and Preferred Mask Type
Authors: Tamara Dörr, Sabine Haller, Maja F. Müller, Andrée Friedl, Danielle Vuichard, Christian R. Kahlert, Philipp Kohler
Journal: JAMA Network Open (2022)

This cohort study compares the risk of infection with SARS-CoV-2 among health care workers by mask preference and level of patient exposure.
Performance of 2 Single-Item Screening Questions to Identify Future Homelessness Among Emergency Department Patients
Authors: Thomas Byrne, Mindy Hoang, Ann Elizabeth Montgomery, Eileen Johns, Marybeth Shinn, Tod Mijanovich, Dennis Culhane, Kelly M. Doran
Journal: JAMA Network Open (2022)

Importance Despite increasing interest in assessing patient social needs in health care settings, there has been little research examining the performance of housing-related screening questions. Objective To examine the performance of 2 single-item screening questions assessing emergency department (ED) patients’ self-perceived risk of future homelessness. Design, Setting, and Participants This prospective cohort study was conducted among a randomly selected sample of adult ED patients from 2016 to 2017 in a public hospital ED in New York City. Data were analyzed from September 2019 through October 2021. Exposures Responses on patient surveys conducted at the baseline ED visit for 2 single-item screening questions on self-perceived risk for future housing instability and homelessness were collected. One question asked patients if they were worried about having stable housing in the next 2 months, and the other question asked them to rate the likelihood that they would enter a homeless shelter in the next 6 months. Outcomes Homeless shelter entry 2, 6, and 12 months after an ED visit, assessed using shelter administrative data in the study city, which was linked with participant baseline survey responses. Results There were 1919 study participants (976 [51.0%] men and 931 [48.6%] women among 1915 individuals with gender data; 700 individuals aged 31-50 years [36.5%] among 1918 individuals with age data; 1126 Hispanic or Latinx individuals [59.0%], 368 non-Hispanic Black individuals [19.3%], and 225 non-Hispanic White individuals [11.8%] among 1908 individuals with race and ethnicity data). Within 2, 6, and 12 months of the ED visit, 45 patients (2.3%), 66 patients (3.4%), and 95 patients (5.0%) had entered shelter, respectively. For both single-item screening questions, participants who answered affirmatively had significantly higher likelihood of future shelter entry at each time point examined (eg, at 2 months: 31 participants responding yes [6.5%] vs 14 participants responding no [1.0%] to the question concerning being worried about having stable housing in the next 2 months). Sensitivity of the screening questions ranged from 0.27 to 0.69, specificity from 0.76 to 0.97, positive predictive value from 0.07 to 0.27, and area under the receiver operating characteristic curve from 0.62 to 0.72. Conclusions and Relevance This study found that 2 single-item screening questions assessing ED patient self-perceived risk of future housing instability and homelessness had adequate to good performance in identifying risk for future shelter entry. Such single-item screening questions should be further tested before broad adoption.
Error in Affiliations
Journal: JAMA Network Open (2022)

Pervez Sultan, MBChB; Kazuo Ando; Rania Elkhateb; Ronald B. George, MD; Grace Lim; Brendan Carvalho, MBBCh; Ahish Chitneni, MD; Ray Kawai; Tanya Tulipan, MD; Lindsay Blake, MLIS; Jessica Coker, MD; James O’Carroll, MBBS
Open Letter to G7 and G20 leaders: resolve global crises to secure our future
Authors: Shashika Bandara, Prativa Baral, Anshumi Joshi, Joy Muhia, Afifah Rahman-Shepherd, Praju Adhikari, Alice Bayingana, Hloni Bookholane, Yara Changyit-Levin, Sara Dada, Rohini Dutta, Mohammad Yasir Essar, Nelson Aghogho Evaborhene, Daniel Krugman, Ramya Kumar, Malvikha Manoj, Kedest Mathewos, Nehemiah Olson, Rhiannon Osborne, Daniel Romero-Alvarez, Zaw Myo Tun, Brian Li Han Wong
Journal: Nature Medicine (2022)
Nuclear morphology is a deep learning biomarker of cellular senescence
Authors: Indra Heckenbach, Garik V. Mkrtchyan, Michael Ben Ezra, Daniela Bakula, Jakob Sture Madsen, Malte Hasle Nielsen, Denise Oró, Brenna Osborne, Anthony J Covarrubias, M. Laura Idda, Myriam Gorospe, Laust Mortensen, Eric Verdin, Rudi Westendorp, Morten Scheibye-Knudsen
Journal: Nature Aging (2022)

Abstract Cellular senescence is an important factor in aging and many age-related diseases, but understanding its role in health is challenging due to the lack of exclusive or universal markers. Using neural networks, we predict senescence from the nuclear morphology of human fibroblasts with up to 95% accuracy, and investigate murine astrocytes, murine neurons, and fibroblasts with premature aging in culture. After generalizing our approach, the predictor recognizes higher rates of senescence in p21-positive and ethynyl-2’-deoxyuridine (EdU)-negative nuclei in tissues and shows an increasing rate of senescent cells with age in H&amp;E-stained murine liver tissue and human dermal biopsies. Evaluating medical records reveals that higher rates of senescent cells correspond to decreased rates of malignant neoplasms and increased rates of osteoporosis, osteoarthritis, hypertension and cerebral infarction. In sum, we show that morphological alterations of the nucleus can serve as a deep learning predictor of senescence that is applicable across tissues and species and is associated with health outcomes in humans.
Paradoxical Effects of Endoplasmic Reticulum Aminopeptidase 1 Deficiency on <scp>HLA</scp>–<scp>B27</scp> and Its Role as an Epistatic Modifier in Experimental Spondyloarthritis
Authors: Tri M. Tran, Tejpal Gill, Joshua Bennett, Sohee Hong, Vance Holt, Anders J. Lindstedt, Sufia Bakshi, Keith Sikora, Joel D. Taurog, Maxime Breban, Fatemeh Navid, Robert A. Colbert
Journal: Arthritis & Rheumatology (2022)

Objective We undertook this study to examine the functional basis for epistasis between endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA–B27 in experimental spondyloarthritis (SpA). Methods ERAP1–knockout rats were created using genome editing and bred with HLA–B27/human β 2 ‐microglobulin–transgenic (HLA–B27‐Tg) rats and HLA–B7‐Tg rats. The effects of ERAP1 deficiency on HLA allotypes were determined using immunoprecipitation and immunoblotting, flow cytometry, allogeneic T cell proliferation assays, and gene expression analyses. Animals were examined for clinical features of disease, and tissue was assessed by histology. Results ERAP1 deficiency increased the ratio of folded to unfolded (β 2 m‐free) HLA–B27 heavy chains, while having the opposite effect on HLA–B7. Furthermore, in rats with ERAP1 deficiency, HLA–B27 misfolding was reduced, while free HLA–B27 heavy chain dimers on the cell surface and monomers were increased. The effects of ERAP1 deficiency persisted during up‐regulation of HLA–B27 and led to a reduction in endoplasmic reticulum stress. ERAP1 deficiency reduced the prevalence of arthritis in HLA–B27‐Tg rats by two‐thirds without reducing gastrointestinal inflammation. Dendritic cell abnormalities attributed to the presence of HLA–B27, including reduced allogeneic T cell stimulation and loss of CD103‐positive/major histocompatibility complex class II–positive cells, were not rescued by ERAP1 deficiency, while excess Il23a up‐regulation was mitigated. Conclusion ERAP1 deficiency reduced HLA–B27 misfolding and improved folding while having opposing effects on HLA–B7. The finding that HLA–B27‐Tg rats had partial protection against SpA in this study is consistent with genetic evidence that loss‐of‐function and/or reduced expression of ERAP1 reduces the risk of ankylosing spondylitis. Functional studies support the concept that the effects of ERAP1 on HLA–B27 and SpA may be a consequence of how peptides affect the biology of this allotype rather than their role as antigenic determinants.
Neoadjuvant Nivolumab Plus Ipilimumab and Adjuvant Nivolumab in Localized Deficient Mismatch Repair/Microsatellite Instability–High Gastric or Esophagogastric Junction Adenocarcinoma: The GERCOR NEONIPIGA Phase II Study
Authors: Thierry André, David Tougeron, Guillaume Piessen, Christelle de la Fouchardière, Christophe Louvet, Antoine Adenis, Marine Jary, Christophe Tournigand, Thomas Aparicio, Jérôme Desrame, Astrid Lièvre, Marie-Line Garcia-Larnicol, Thomas Pudlarz, Romain Cohen, Salomé Memmi, Dewi Vernerey, Julie Henriques, Jérémie H. Lefevre, Magali Svrcek
Journal: Journal of Clinical Oncology (2022)

In patients with resectable gastric/gastroesophageal junction (GEJ) adenocarcinoma, surgery plus perioperative platinum-based chemotherapy is the standard of care. Perioperative chemotherapy remains debatable for gastric/GEJ adenocarcinoma with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H).NEONIPIGA (ClinicalTrials.gov identifier: NCT04006262) phase II study evaluated neoadjuvant nivolumab 240 mg once every two weeks ×6 and ipilimumab 1 mg/kg once every six weeks ×2, followed by surgery and adjuvant nivolumab 480 mg once every four weeks (nine injections) in patients with locally advanced resectable dMMR/MSI-H, clinical (c) tumor (T)2-T4 node (N)x metastasis (M)0 gastric/GEJ adenocarcinoma. The primary end point was a pathological complete response (pCR) rate.Between October 2019 and June 2021, 32 patients with dMMR/MSI-H gastric/GEJ adenocarcinoma were enrolled. The median age was 65.5 years (range, 40-80). Clinical stages were cT2-T3N0 (n = 9), cT2-T3N1 (n = 22), and cT3N1M1 (n = 1, wrongly included). With a median follow-up of 14.9 months (95% CI, 10.6 to 17.6), 32 patients received neoadjuvant immunotherapy (27 patients completed all cycles). Neoadjuvant therapy-related grade 3/4 adverse events occurred in six patients (19%). Twenty-nine patients underwent surgery; three did not have surgery and had complete endoscopic response with tumor-free biopsies and a normal computed tomography scan (two refused surgery and one had metastasis at inclusion). The rate of surgical morbidity (Clavien-Dindo classification) was 55% (one postoperative death occurred). All 29 patients had an R0 resection, and 17 (58.6%; 90% CI, 41.8 to 74.1) had pCR (pathological T0N0). Becker tumor regression grades 1a, 1b, 2, and 3 were observed in 17 patients, three (including two pathological T0N1), two, and seven patients, respectively. Of the 29 patients with surgery, 23 received adjuvant nivolumab. At database lock, no patient had relapse and one died without relapse.Nivolumab and ipilimumab-based neoadjuvant therapy is feasible and associated with no unexpected toxicity and a high pCR rate in patients with dMMR/MSI-H resectable gastric/GEJ adenocarcinoma.
Annals Consult Guys - Endocarditis Prophylaxis for Patients With TAVR
Authors: Howard H. Weitz, Geno J. Merli
Journal: Annals of Internal Medicine (2022)

Web ExclusivesAugust 2022Annals Consult Guys - Endocarditis Prophylaxis for Patients With TAVRFREEHoward H. Weitz, MD and Geno J. Merli, MDHoward H. Weitz, MDThomas Jefferson University, Philadelphia, Pennsylvania (H.H.W., G.J.M.)Search for more papers by this author and Geno J. Merli, MDThomas Jefferson University, Philadelphia, Pennsylvania (H.H.W., G.J.M.)Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W21-0009 CME/MOC SectionsSupplemental MaterialAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail The Annals Consult Guys discuss the management of a 78-year-old man who received a TAVR 3 months previously and will be having a screening colonoscopy and a dental extraction. They discuss various options for antiplatelet therapy and infection prophylaxis in the setting of these procedures.For more videos from and information on Annals Consult Guys, visit go.annals.org/ConsultGuys. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Thomas Jefferson University, Philadelphia, Pennsylvania (H.H.W., G.J.M.)Disclosures: Drs. Merli and Weitz report that they have no financial relationships or interests to disclose. All relevant financial relationships have been mitigated. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=W21-0009.Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Stephanie Chang, MD, MPH, Deputy Editor, reports employment with the Agency for Healthcare Research and Quality, travel compensation from the Guidelines International Network, and participation in the Patient-Centered Outcomes Research Institute methodology committee. Vineet Chopra, MD, MSc, Deputy Editor, reports grants received from the Agency for Healthcare Research and Quality and royalties from UpToDate and Oxford University Press. Deborah Cotton, MD, MPH, Deputy Editor, reports that she has no financial relationships or interests to disclose. Eliseo Guallar, MD, MPH, DrPH, Deputy Editor, Statistics, reports that he is employed at Johns Hopkins University. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center and consultancy with Boston Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports employment with the Perelman School of Medicine, University of Pennsylvania, and consultancies with the U.S. Food and Drug Administration and the State of Colorado. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics August 2022Volume 175, Issue 8Page: CG1 ePublished: 16 August 2022 Issue Published: August 2022 CopyrightCopyright © 2022 by American College of Physicians. All Rights Reserved.Loading ...
Impact of Medication Nonadherence in a Clinical Trial of Dual Antiplatelet Therapy
Authors: Marco Valgimigli, Enrico Frigoli, Pascal Vranckx, Yukio Ozaki, Marie-Claude Morice, Bernard Chevalier, Yoshinobu Onuma, Stephan Windecker, Laurent Delorme, Petr Kala, Sasko Kedev, Rajpal K Abhaichand, Vasil Velchev, Willem Dewilde, Jakub Podolec, Gregor Leibundgut, Dragan Topic, Carl Schultz, Goran Stankovic, Astin Lee, Thomas Johnson, Pim A L Tonino, Aneta Klotzka, Maciej Lesiak, Renato D Lopes, Pieter C Smits, Dik Heg
Journal: Journal of the American College of Cardiology (2022)
Comparison of the Effects of Over-the-counter Famotidine and Calcium Carbonate Antacid on Postprandial Gastric Acid
Authors: Mark Feldman
Journal: JAMA (1996)

<h3>Objective.</h3> —To compare an over-the-counter histamine<sub>2</sub>-receptor antagonist with an antacid as gastric acid reducers. <h3>Design.</h3> —Randomized, double-blind, placebo-controlled crossover trial. <h3>Setting.</h3> —Gastric secretory research laboratory in a Veterans Affairs medical center. <h3>Participants.</h3> —Eighteen healthy volunteers (10 men and 8 women) aged 25 to 62 years with normal gastric acid secretion rates. <h3>Interventions.</h3> —The subjects received the histamine2-receptor antagonist famotidine (Pepcid AC, 10 mg), calcium carbonate antacid tablets (Turns, 1000 mg), or placebo medications 1 hour after a test meal. Two identical meals were taken 2.5 and 6.0 hours after the medication was given. <h3>Main Outcome Measures.</h3> —Intragastric pH was maintained at 4.0 by in vivo intragastric titration with 0.3N sodium bicarbonate for 10 hours (1 hour before and 9 hours after medication). Reduction in sodium bicarbonate titrant use in the 2 treatment groups compared with titrant use with placebo was reflective of acid secretion inhibited by famotidine or acid neutralized by calcium carbonate tablets. <h3>Results.</h3> —When evaluated in increments of 30 minutes, calcium carbonate had a rapid onset of action, neutralizing 6.7 mmol of acid in the first 30 minutes. However, its duration of effect was only 60 minutes. Famotidine had a delayed onset of action compared with antacid, beginning after 90 minutes. However, famotidine had a duration of effect of at least 540 minutes. At its peak effect, 210 minutes after administration, famotidine reduced acid secretion by 7.3 mmol per 30 minutes. <h3>Conclusions.</h3> —Recommended over-the-counter doses of famotidine and calcium carbonate tablets have different pharmacokinetic profiles when taken in the postprandial period. The antacid has a rapid onset and short duration of action, while the histamine<sub>2</sub>-receptor antagonist has a delayed onset and a prolonged duration. Their peak potencies are similar. (<i>JAMA</i>. 1996;275:1428-1431)
Intensity and longevity of SARS-CoV-2 vaccination response in patients with immune-mediated inflammatory disease: a prospective cohort study
Authors: David Simon, Koray Tascilar, Filippo Fagni, Arnd Kleyer, Gerhard Krönke, Christine Meder, Peter Dietrich, Till Orlemann, Johanna Mößner, Jule Taubmann, Melek Yalcin Mutlu, Johannes Knitza, Stephan Kemenes, Anna-Maria Liphardt, Verena Schönau, Daniela Bohr, Louis Schuster, Fabian Hartmann, Ioanna Minopoulou, Moritz Leppkes, Andreas Ramming, Milena Pachowsky, Florian Schuch, Monika Ronneberger, Stefan Kleinert, Axel J Hueber, Karin Manger, Bernhard Manger, Raja Atreya, Carola Berking, Michael Sticherling, Markus F Neurath, Georg Schett
Journal: The Lancet Rheumatology (2022)